Clostridial Neurotoxins

Verastegui, Carole; Lalli, Giovanna; Bohnert, Stephanie; Meunier, Frédéric A.; Schiavo, Giampietro

doi:10.1081/txr-120014404

Cited by 5 publications

(5 citation statements)

References 118 publications

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“…34 All BoNTs are synthesized as 150 kDa single chain propeptides that accumulate in the cytosol of the bacterial cell until they are released by cell autolysis. 35 This polypeptide is selectively cleaved by intra-or extracellular proteases to produce an active two-chain BoNT consisting of a heavy chain domain (100 kDa) and a light chain domain (50 kDa) joined by one or more disulfide linkages. Initially, BoNT is associated with nontoxic bacterial proteins in a large, stable complex known as the progenitor toxin (y900 kDa) that serves to protect the toxin from the denaturing environment of the stomach.…”

Section: Botulismmentioning

confidence: 99%

“…Consistent with other bacterial protein toxins including anthrax, BoNT intoxication occurs through a multi-step process involving binding, internalization, membrane translocation, and intracellular catalytic activity. 35 BoNT binds to a neuronal cell surface receptor through its heavy chain domain and is subsequently internalized by receptor-mediated endocytosis. Once internalized, a BoNT disulfide bond is reduced and the neurotoxin light chain is released from the vesicle into the cytosol.…”

Section: Botulismmentioning

confidence: 99%

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Technological advancements for the detection of and protection against biological and chemical warfare agents

2007

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There is a growing need for technological advancements to combat agents of chemical and biological warfare, particularly in the context of the deliberate use of a chemical and/or biological warfare agent by a terrorist organization. In this tutorial review, we describe methods that have been developed both for the specific detection of biological and chemical warfare agents in a field setting, as well as potential therapeutic approaches for treating exposure to these toxic species. In particular, nerve agents are described as a typical chemical warfare agent, and the two potent biothreat agents, anthrax and botulinum neurotoxin, are used as illustrative examples of potent weapons for which countermeasures are urgently needed.

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Section: Botulismmentioning

confidence: 99%

Section: Botulismmentioning

confidence: 99%

Technological advancements for the detection of and protection against biological and chemical warfare agents

2007

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“…Botulinum neurotoxin type-A (BoNT/A) is a highly potent neurotoxin that acts at the level of presynaptic motor nerve terminals, binding both gangliosides and a protein acceptor in order to be endocytosed 1 2 3 4 . Following translocation from the acidic endosomal compartment, the BoNT/A light chain, which displays endopeptidase activity, cleaves SNAP-25, thereby inducing flaccid paralysis 5 6 7 8 9 .…”

mentioning

confidence: 99%

Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles

Harper

Papadopulos

Martin

et al. 2016

Sci Rep

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Neuronal communication relies on synaptic vesicles undergoing regulated exocytosis and recycling for multiple rounds of fusion. Whether all synaptic vesicles have identical protein content has been challenged, suggesting that their recycling ability may differ greatly. Botulinum neurotoxin type-A (BoNT/A) is a highly potent neurotoxin that is internalized in synaptic vesicles at motor nerve terminals and induces flaccid paralysis. Recently, BoNT/A was also shown to undergo retrograde transport, suggesting it might enter a specific pool of synaptic vesicles with a retrograde trafficking fate. Using high-resolution microscopy techniques including electron microscopy and single molecule imaging, we found that the BoNT/A binding domain is internalized within a subset of vesicles that only partially co-localize with cholera toxin B-subunit and have markedly reduced VAMP2 immunoreactivity. Synaptic vesicles loaded with pHrodo-BoNT/A-Hc exhibited a significantly reduced ability to fuse with the plasma membrane in mouse hippocampal nerve terminals when compared with pHrodo-dextran-containing synaptic vesicles and pHrodo-labeled anti-GFP nanobodies bound to VAMP2-pHluorin or vGlut-pHluorin. Similar results were also obtained at the amphibian neuromuscular junction. These results reveal that BoNT/A is internalized in a subpopulation of synaptic vesicles that are not destined to recycle, highlighting the existence of significant molecular and functional heterogeneity between synaptic vesicles.

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“…Exposure to toxin prevents the release of acetylcholine at neuromuscular junctions and synapses by cleaving one of the three neuronal proteins of the soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) complex required for synaptic vesicle membrane fusion resulting in flaccid muscle paralysis. [1][2][3][4] Ironically, these toxins are used clinically to treat neuromuscular disorders.…”

Section: Introductionmentioning

confidence: 99%